Class II HLA interactions modulate genetic risk for multiple sclerosis

By L. Moutsianas, L. Jostins, Ashley H Beecham, A. Dilthey, Dionysia K. Xifara, M. Ban, T. Shah, N. Patsopoulos, L. Alfredsson, C. Anderson and 46 more. 2015

366 citations recorded by the source corpus.

Association studies have greatly refined the understanding of how variation within the human leukocyte antigen (HLA) genes influences risk of multiple sclerosis. However, the extent to which major effects are modulated by interactions is poorly characterized. We analyzed high-density SNP data on 17,465 cases and 30,385 controls from 11 cohorts of European ancestry, in combination with imputation of classical HLA alleles, to build a high-resolution map of HLA genetic risk and assess the evidence for interactions involving classical HLA alleles. Among new and previously identified class II risk alleles (HLA-DRB1*15:01, HLA-DRB1*13:03, HLA-DRB1*03:01, HLA-DRB1*08:01 and HLA-DQB1*03:02) and class I protective alleles (HLA-A*02:01, HLA-B*44:02, HLA-B*38:01 and HLA-B*55:01), we find evidence for two interactions involving pairs of class II alleles: HLA-DQA1*01:01–HLA-DRB1*15:01 and HLA-DQB1*03:01–HLA-DQB1*03:02. We find no evidence for interactions between classical HLA alleles and non-HLA risk-associated variants and estimate a minimal effect of polygenic epistasis in modulating major risk alleles.

Subfields: Immunology, Pathology and Forensic Medicine, Rheumatology

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. T. Korn
2. Roland Martin
3. David A. Hafler
4. Howard L. Weiner
5. L. Piccio
6. Hakon Hakonarson
7. J. Buckner
8. C. Iadecola

In Pathology and Forensic Medicine

1. Stephen L. Hauser
2. Jorge R. Oksenberg
3. T. Korn
4. B. Cree
5. Roland Martin
6. David A. Hafler
7. Sandra Vukusic
8. Hans Lassmann

In Rheumatology

1. Stephen L. Hauser
2. Hakon Hakonarson
3. Sandra Vukusic

Citations in the corpus

• Multiple Sclerosis Genomic Map implicates peripheral immune cells & microglia in susceptibility (2019, background): “The MHC was the first MS susceptibility locus to be identified, and prior studies have found that theMHC harbors multiple independent susceptibility variants, including interactions within the class II human leukocyte antigen (HLA) genes (16, 17).”
• HLA variation and disease (2018, background): “…trans 81 , whereas for multiple sclerosis, the protective effect of the HLA‑DQA1*01:01 haplotype in carriers of the disease­associated HLA‑DRB1*15:01 genotype 30 may be related to TCR cross reactivity, as pro­ posed for another multiple­sclerosis­related interaction — HLA‑DRB1*15:01–HLA‑DRB5 (REF.”